This is an integrated neuroinformatics project with two long-term objectives: i) to develop and rigorously to evaluate innovative methods for analysis of functional magnetic resonance imaging (fMRI) experiments using wavelets and data resampling as key mathematical tools; ii) to enhance characterization of brain adaptivity to task repetition and variable task difficulty and to test explicit hypotheses concerning effects of normal aging and transmitter-specific drug treatments on brain adaptivity. The key informatics objectives are i) to refine and apply a new best linear unbiased estimator of regression model parameters in the context of long-memory noise (wavelet-generalized least squares); ii) to consolidate and evolve methods for multiresolutional analysis of spatially extended 2- or 3-dimensional processes using wavelets and data resampling; iii) to implement multiscale image registration in the wavelet domain as a framework in which to assess the impact of variably precise image registration on mixed effects modeling of grouped and factorially designed fMRI datasets; iv) to explore 4-dimensional wavelet shrinkage as a novel adjunct or alternative to our ongoing interest in multivariate methods of connectivity analysis; and v) to develop and cross-validate estimators of spectral exponents, fractal dimensions and other complexity measures in fMRI. These informatics objectives are critical to a comprehensive and powerful analysis of drug and aging effects on brain adaptivity and fMRI noise - which are the focus of three key neuroscientific experiments: i) we will test the assumption that fMRI noise has l/f-like spectral properties, and investigate instrumental and physiological sources for 1/f noise, using phantom and biological "resting" fMRI data; ii) we will develop and validate a set of cognitive activation paradigms focused on adaptivity to repetition and load in several domains of memory and learning; and iii) we will conduct a major (N=48) factorially designed pharmacological MRI study in young (aged 20-30 years) and older (aged 60-70 years) healthy participants each scanned on three occasions in a randomized, placebo-controlled experiment. These data will allow us to test hypotheses concerning the main effects of agonist and antagonist drugs targeted on dopaminergic, cholinergic and GABAergic transmitter systems and thereby to elucidate mechanisms for large-scale brain adaptivity. We will also test hypotheses concerning the main effect of aging and the interactive effect of drugs and age on brain adaptivity.